Dissecting the mammary stem cell hierarchy and its molecular regulators (#1)
To understand relationships between breast tissue and ‘cells of origin’ of cancer in breast tumors, it is necessary to dissect the normal mammary epithelial hierarchy. We have isolated discrete populations of mouse and human mammary epithelial cells on the basis of cell surface markers and identified subsets that are enriched for mammary stem cells (MaSCs), luminal progenitor and mature luminal cells. Recent studies have revealed that MaSCs are highly responsive to steroid hormones despite lacking expression of the estrogen and progesterone receptors. Transcriptome analyses of mouse and human mammary epithelial populations have led to the identification of multiple conserved genes/pathways and potential effectors of hormone action. In addition, the roles of a number of transcriptional regulators have been pinpointed along the mammary hierarchy using targeted mice. High throughput functional shRNA screens are currently being performed to identify novel genes governing stem cell proliferation and differentiation. To extend these studies, we have determined the epigenomes of primary mammary epithelial subtypes. Comparison of the whole-genome histone modification maps with the transcriptomes of these subpopulations in different hormonal settings will provide insight into molecular mechanisms that control cell-fate and differentiation programs in stem and progenitor cells.